In recent decades, transient and highly reactive ortho-quinodimethanes (o-QDMs), ortho-quinone methides (o-QMs) and aza-ortho-quinone methides (aza-o-QMs) have attracted much attention and have been extensively studied and applied in organic synthesis, especially natural product total synthesis. This review summarizes recent advances in Diels-Alder reactions involving in situ-generated o-QDMs, o-QMs and aza-o-QMs, highlighting the power and potential of this strategy in organic synthesis and natural product total synthesis. An overview of the methods for generating these intermediates is also available.

Cycloaddition is an essential tool in chemical synthesis. Instead of using light or heat as a driving force, marine sponges promote cycloaddition with a more versatile but poorly understood mechanism in producing pyrrole–imidazole alkaloids sceptrin, massadine, and ageliferin. Through de novo synthesis of sceptrin and massadine, we show that sponges may use single-electron oxidation as a central mechanism to promote three different types of cycloaddition. Additionally, we provide surprising evidence that, in contrast to previous reports, sceptrin, massadine, and ageliferin have mismatched chirality. Therefore, massadine cannot be an oxidative rearrangement product of sceptrin or ageliferin, as is commonly believed. Taken together, our results demonstrate unconventional chemical approaches to achieving cycloaddition reactions in synthesis and uncover enantiodivergence as a new biosynthetic paradigm for natural products.

This review will focus on selected applications of Sonogashira coupling and subsequent transformations as key steps in the total synthesis of natural products.

This manuscript describes a convergent synthesis and the revision of the relative stereochemistry of nakiterpiosin, a marine C-nor-D-homosteroid. Our synthesis features a late-stage carbonylative Stille cross-coupling reaction and a photo-Nazarov cyclization reaction that deliver the complete nakiterpiosin skeleton efficiently. Nakiterpiosin (1) is a marine sponge metabolite that exhibits potent cytotoxicity against the P388 murine leukemia cell line (GI 50 10 ng/mL) ( Figure 1). 1 It was the first C-nor-Dhomosteroid isolated from a marine source. Its unique chemical structure and strong P388 growth inhibition property prompted us to initiate a research program to explore its laboratory synthesis 2 and biological function. We report herein the synthesis and structure revision 3 of nakiterpiosin.The C-nor-D-homosteroids are skeletally rearranged steroids with their C-ring contracted and D-ring expanded by one carbon. The veratrum alkaloid cyclopamine (3) and veratramine (4) are arguably the best known members. 4,5 The teratogenic alkaloid 3 inhibits the Hedgehog (Hh) signaling by binding to Smoothened (Smo), 6,7 and the chronotropic alkaloid 4 induces serotonin (5-HT) syndrome. 8 While 1 possesses potent cytotoxicity against P388, its molecular target is not known. Furthermore, the complete biological profile of 1 could not be obtained due to the scarcity of the material. From 30 kg of sponge T. hoshinota, only 0.4 mg of nakiterpiosin was obtained. Its chemical structure was assigned as 2 in the original reports. 1We were puzzled by the inconsistency between the C-20 stereochemistry reported for 2 and 3/4 and therefore set out to probe the relative stereochemistry of nakiterpiosin. Our model studies indicated potential misassignment of the C-6, C-20 and C-25 stereogenic centers. 9 We next considered the biogenesis of the halogen atoms 10 of nakiterpiosin to rationalize the C-6 and C-20 stereochemistry. We envisioned that the C-21 chlorine atoms of nakiterpiosin might be introduced by radical chlorination and the C-6 bromine atom by bromoetherification (as shown in 5) to result in retention of the C-20 configuration and the anti C-5,6 bromohydrin stereochemistry. Taken together, these considerations led us to propose 1 to be the correct structure of nakiterpiosin. Indeed, we found that the 1 H and 13 C NMR spectra of our synthetic sample of 1 agreed with those of the natural product. 11 In contrast, those of synthetic 2 9,11 and the natural product are significantly different. We thus revised the relative stereochemistry Chuo.Chen@UTSouthwestern.edu. NIH Public AccessAuthor Manuscript J Am Chem Soc. Author manuscript; available in PMC 2010 February 4. Our synthetic strategy is outlined in Figure 2. We dissected 1 into fragments 6 and 7 and constructed the central cyclopentanone ring with a carbonylative cross-coupling reaction 12 and a photo-Nazarov cyclization reaction. 13 The electrophilic coupling component 6 was synthesized by an intramolecular Diels-Alder reaction, 14 and the nucleophilic coupling com...

The first total synthesis of cyanthiwigins A, C, H and concise synthesis of cyanthiwigin G was achieved from a common intermediate. A modified formal [4 + 2] cycloaddition was developed to construct the key cis-hydrindanone (A-B). Stereospecific 1,4-addition, alkylation, and ring-closing metathesis were used to build the tricarbocyclic ring system (A-B-C). Various site-selective oxidations were applied to create the desired oxidation states of the different cyanthiwigins.

Covering: 2006 to 2015C-H functionalization remains one of the frontier challenges in organic chemistry and drives quite an active area of research. It has recently been applied in various novel strategies for the synthesis of natural products. It can dramatically increase synthetic efficiency when incorporated into retrosynthetic analyses of complex natural products, making it an essential part of current trends in organic synthesis. In this Review, we focus on selected case studies of recent applications of C-H oxidation methodologies in which the C-H bond has been exploited effectively to construct C-O and C-N bonds in natural product syntheses. Examples of syntheses representing different types of C-H oxidation are discussed to illustrate the potential of this approach and inspire future applications.

The synthetic approach to the core framework of the calyciphylline A-type Daphniphyllum alkaloids and total synthesis of himalensine A were described herein. Nitrone-induced 1,3-dipolar [3 + 2] cycloaddition was applied for the construction of A/C rings along with the all-carbon quaternary center. Pd-catalyzed enolate alkenylation and ring closing metathesis (RCM) were adopted to install the B/D rings to accomplish the [6,6,5,7] core framework. Nazarov reaction was utilized to install the F ring to complete the total synthesis of himalensine A.

Starting from equisetin, the asymmetric synthesis of (+)-fusarisetin A has been accomplished in a one-pot transformation including a biomimetic oxidation and an intramolecular Diels-Alder/Roskamp reaction. Peroxyfusarisetin is proposed as a plausible biosynthetic intermediate based on studies of the oxidation of equisetin.